Chemotherapy and radiotherapy of metastatic cancer, because of toxicity to both normal and abnormal tissues, present the clinician with the difficult challenge of trying to kill the neoplastic disease before killing the patient; a balance between treatment and rescue. All traditional cancer treatments are associated with toxicity, an increase in morbidity, and a reduction in quality of life that may extend far beyond the period of treatment. A major focus of current anti-neoplastic treatments is targeting treatment to the cancer cells, for example, targeting proteins expressed or over-expressed by cancer cells, but not by normal tissue.
Many invasive cancer cell types over-express voltage-gated sodium channels (VGSCs; or “sodium channels”) by more than 1000-fold greater than normal cells (1, 2, 7). Cancer cells that over-express VGSCs are epithelial carcinomas that include, but are not limited to, highly invasive breast cancer (4, 10, 13, 27), prostate cancer (2, 6, 7, 8, 18, 19, 20, 21, 22, 26), small cell lung cancer (3, 23), non-small cell lung carcinoma (28), lymphoma (9), neuroblastoma (25), and cervical cancer (5). Mesothelioma which is not classified as an epithelial cancer is also known to over-express VGSCs (12). When these sodium channels are activated, Na+ is conducted into the cells. In these cancers, the degree of metastasis is directly related to an increased expression of VGSCs (1, 7; see also U.S. Pat. No. 7,393,657). Physiologically, these cancer cells share certain cellular properties with normal excitable cells such as neurons and cardiac myocytes (for example, the conduction of action potentials). U.S. Pat. No. 7,393,657 discloses the use of inhibitors of VGSCs as a treatment for cancer, including breast cancer.
Of the 1.6 million people contracting epithelial cell cancer each year in the U.S., 40% are considered to be “highly invasive” and over-express VGSCs (10). These patients diagnosed with malignant/metastatic carcinomas are treated currently with major and often disfiguring surgical procedures, chemotherapy and/or radiation. More than 400,000 people die from epithelial cell carcinoma each year in the United States and an estimated 10 times that world-wide. In addition, another 1,200,000 U.S. patients diagnosed with invasive cancer are successfully treated with traditional surgery, chemotherapy and/or radiation. Breast cell carcinoma is an example of a highly invasive cancer. More than 40,000 people die from breast cell carcinoma each year in the United States and 465,000 world-wide. Greater than 90% of these deaths are due to metastasis of the primary tumor. In addition, another 170,000 U.S. women diagnosed with invasive breast cancer are successfully treated with traditional mastectomy, lumpectomy, chemotherapy and/or radiation. Of the 207,000 people contracting breast cancer each year, 40% of the cancers are considered to be “highly invasive”, and over-express VGSCs (10).
The family of sodium channels named “voltage-gated sodium channels” was so designated due to the sensitivity to small changes (>40 mV) in the voltage gradient across the cellular membrane. They have also been shown to be activated by many forms of stimulation—mechanical disturbances in the membrane, ultrasound (29), magnetic fields (29), and several drugs. There are nine members of the VGSC family, with variants of many of the isoforms. They are designated Nav1.X, where X represents 1-9. Subtypes are designated with a letter a, b, etc.
Na+, K+-ATPase is a ubiquitous transmembrane protein in animal cells, and functions to maintain an ion imbalance across the cell membrane where more charged ions are located outside of the cell, largely sodium ions, than inside. This produces an electrochemical gradient that is in homeostatic balance. When ionic imbalance shifts in the presence of a change in voltage an action potential is generated causing a transient osmotic shift toward an intracellular hypertonic state. The restoration of the sodium imbalance is an essential function performed by Na+, K+-ATPase. When Na+, K+-ATPase does not function properly, water follows sodium into the cell to restore osmotic balance thereby increasing cell volume. In normal cells this shift in cell volume is tolerated due to membrane compliance. Blocking Na+, K+-ATPase function can lead to a loss of cellular excitability and an increase in cellular volume. Many inhibitors are known, including the cardiac glycosides. The isozymes vary in their sensitivity to each of the cardiac glycoside drugs. More than 30 drugs have been shown to inhibit sodium pump activity. These include ouabain, digitalis and its active ingredients digoxin and digitoxin.
U.S. Patent Application Publication No. 2007/0105790 discloses the use of cardiac glycosides (e.g., ouabain and proscillaridin) either alone or in combination with other standard cancer therapeutic agents to treat pancreatic cancers by causing cell apoptosis.
U.S. Patent Application Publication No. 2009/0018088 discloses the use of cardiac glycosides, including digoxin and ouabain, to induce cell apoptosis as a treatment for cancer.